Llorente Cristina, Raya Tonetti Fernanda, Bruellman Ryan, Brea Rocío, Pell Nuria, Hartmann Phillipp, Maccioni Luca, Han Hui, Cabré Noemí, Liu Junlai, Eguileor Alvaro, Fondevila Marcos F, Meijnikman Abraham S, Hsu Cynthia L, Alghafri Ameera, Zhou Rongrong, Gao Bei, Duan Yi, Zhang Peng, Febbraio Mark A, Taniguchi Koji, Newberry Rodney D, Fouts Derrick E, Brenner David A, Stärkel Peter, Karin Michael, Schnabl Bernd
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Nature. 2025 Aug 20. doi: 10.1038/s41586-025-09395-z.
Alcohol-use disorder and alcohol-associated liver disease (ALD) are major causes of death and liver transplantation. The gut-liver axis has a crucial yet poorly understood role in ALD pathogenesis, which depends on microbial translocation. Intestinal goblet cells (GCs) educate the immune system by forming GC-associated antigen passages (GAPs) on activation of muscarinic acetylcholine receptor M4 (mAChR4, also known as M), enabling sampling of luminal antigens by lamina propria antigen-presenting cells. Here we show that chronic alcohol use in humans and mice downregulates small intestinal mAChR4 and reduces GAP formation, disrupting antimicrobial immunity. This is reversed on activation of intestinal IL-6 signal transducer (IL6ST, also known as glycoprotein 130; gp130), which restores mAChR4 expression and GAP formation, enabling induction of downstream type-3 innate lymphoid cell-derived IL-22 and antimicrobial REG3 proteins. This blunts translocation of enteric bacteria to the liver, thereby conferring ALD resistance. GAP induction by GC-specific mAChR4 activation was essential and sufficient for prevention of ethanol-induced steatohepatitis. These results lay the foundation for a therapeutic approach using mAChR4 or IL6ST agonists to promote GAP formation and prevent ALD by inhibiting microbial translocation.
酒精使用障碍和酒精性肝病（ALD）是导致死亡和肝移植的主要原因。肠-肝轴在ALD发病机制中起着关键但尚未完全了解的作用，其发病机制取决于微生物易位。肠道杯状细胞（GCs）通过在毒蕈碱型乙酰胆碱受体M4（mAChR4，也称为M）激活时形成与GC相关的抗原通道（GAPs）来调节免疫系统，使固有层抗原呈递细胞能够对腔内抗原进行采样。在这里，我们表明，人类和小鼠长期饮酒会下调小肠中的mAChR4并减少GAP形成，从而破坏抗菌免疫。激活肠道白细胞介素6信号转导子（IL6ST，也称为糖蛋白130；gp130）后，这种情况会逆转，从而恢复mAChR4表达和GAP形成，进而诱导下游3型天然淋巴细胞衍生的白细胞介素22和抗菌REG3蛋白。这减少了肠道细菌向肝脏的易位，从而赋予对ALD的抗性。通过GC特异性激活mAChR4诱导GAP对于预防乙醇诱导的脂肪性肝炎至关重要且足够。这些结果为使用mAChR4或IL6ST激动剂促进GAP形成并通过抑制微生物易位来预防ALD的治疗方法奠定了基础。
